Abstract The objective of this study is to characterize a recently identified tumor-associated gene, HBXAP (also known as Rsf-1), that is amplified in ovarian cancer. Over the past years, we have applied genome-wide analyses to delineate molecular genetic changes in ovarian cancer, and have identified a new amplified gene, HBXAP (Rsf-1), in ovarian carcinomas. Amplification and overexpression of HBXAP are significantly associated with the most aggressive type of ovarian cancer in clinical specimens. It has been known that HBXAP interacts with hSNF2H to form a chromatin remodeling complex. Indeed, we demonstrated that HBXAP co- immunoprecipitated with hSNF2H in ovarian caner cells, and expression of HBXAP promoted tumor cell growth and survival in p53 mutated cells but not in p53 wild-type cells. Based on the above findings, we hypothesize that p53 mutation facilitates cells to evade from the oncogene-induced growth suppression and apoptosis, and in the p53 mutant cells, increased HBXAP levels contributes to tumor progression by its binding to hSNF2H. Furthermore, HBXAP may serve as a potential therapeutic target in a preclinical mouse tumor model. To test the above hypotheses, we propose four closely integrated aims. Aim 1: Determine if formation of the HBXAP and hSNF2H chromatin remodeling complex is required for survival in ovarian cancer cells with HBXAP overexpression. Aim 2: Assess the roles of p53 mutations in HBXAP-induced tumor promotion. Aim 3: Assess if overexpression of HBXAP in combination with mutant p53 is essential for tumorigenesis and/or tumor progression. Aim 4: Determine the anti-tumor effects by targeting HBXAP in mouse ovarian cancer xenografts. Revealing the molecular context in deciphering the functions of a tumor-promoting gene is essential to understand the pathogenesis of cancer development and may have translational implications for new cancer therapy. Narrative Previous studies have shown that amplification and overexpression of HBXAP, a chromatin remodeling gene, are significantly associated with the most aggressive type of ovarian cancer. The objective of the current study is to characterize how HBXAP upregulation contributes to the development and progression of ovarian cancer. Revealing the molecular context in deciphering the functions of a tumor-promoting gene is essential to understand the pathogenesis of cancer development and may have translational implications for new cancer therapy.